Enhancing effects of simultaneous treatment with sodium nitrite on 2‐amino‐3‐methylimidazo[4,5‐f]quinoline‐induced rat liver, colon and Zymbal's gland carcinogenesis after initiation with diethylnitrosamine and 1,2‐dimethylhydrazine

Abstract

Combined effects of sodium nitrite (NaNO 2 ) and 2-amino-3-methylimidazo [4,5-f]quinoline (IQ) on liver, colon and Zymbal's gland carcinogenesis were assessed using a rat two-stage carcinogenesis model, with a focus on involvement of oxidative stress. Male 6-week-old F344 rats were given a single intraperitoneal injection of 200 mg/kg of diethylnitrosamine and 4 subcutaneous injections of 40 mg/kg of 1,2-dimethylhydrazine for initiation. Then, they were administered 0 or 300 ppm IQ in the diet or 0, 0.1 or 0.2% NaNO 2 in their drinking water for 27 weeks. The treatment with NaNO 2 1 IQ significantly enhanced colon and Zymbal's gland carcinogenesis and tended to enhance hepatocarcinogenesis. The incidence of lung tumors in the IQ-treated groups was significantly increased as compared with the initiation alone group. In a second experiment, male rats were given IQ or NaNO 2 under the same conditions as before for 1 week, and at sacrifice, their liver and colon tissue or mucosa were collected for analysis of 8-hydroxydeoxyguanosine (8-OHdG), thiobarbituric acid reactive substances (TBARS), acrolein-modified protein and the bromodeoxyuridine-labeling index (BrdU-LI) (in the colon). In the colon, 8-OHdG, acrolein-modified protein levels and BrdU-LI were significantly increased by the combined treatment. These results indicate that the treatment with NaNO 2 enhances IQ-induced colon and Zymbal's gland carcinogenesis in rats and that oxidative DNA damage and lipid peroxidation may partly be involved, especially in the colon. In addition, this experiment showed that IQ can act as a potent lung carcinogen in rats. ' 2005 Wiley-Liss, Inc.Key words: sodium nitrite; 2-amino-3-methylimidazo[4,5-f]quinoline; liver carcinogenesis; colon carcinogenesis; oxidative stress 2-Amino-3-methylimidazo[4,5-f]quinoline (IQ), one of the mutagenic and carcinogenic heterocyclic amines (HCA), has been detected in cooked meat and fish 1 and also in cigarette smoke condensate.2 Long-term experiments using rodents have demonstrated that IQ is carcinogenic to the liver, colon, small intestine, Zymbal's gland, clitoral gland and skin in F344 rats 3 and to the liver, forestomach and lung in CDF 1 mice. 4 Metabolically activated IQ forms DNA adducts in liver of rats, mice and monkeys in vivo 1 and in bacteria in vitro.5 In F344 rats, IQ-specific DNA adducts have been detected in the lungs, kidneys, stomach, large intestine, white blood cells and small intestine.6 It was recently suggested that oxidative stress may also participate in HCA carcinogenesis, based on the finding that HCA-induction of preneoplastic or neoplastic lesions was significantly inhibited when antioxidants were given simultaneously 7,8 and that superoxide anion radicals were generated during NADPH/cytochrome P-450 reductase-mediated metabolic activation of HCAs in vitro using a spin-trapping method. 9Sodium nitrite (NaNO 2 ) is used as a color fixative and preservative for meats and fish, and it is also present in vegetables. 10Although it is generally accepted that NaNO 2 is n...

Edaravone Inhibits DNA Peroxidation and Neuronal Cell Death in Neonatal Hypoxic-Ischemic Encephalopathy Model Rat

“…The 8-OHdG levels of cerebral cortex were measured with a method previously described (23,24). Briefly, nuclear DNA was isolated with a DNA extractor WB kit (Wako Pure Chemical Industries, Osaka, Japan) and digested into deoxynucleotides by treatment with nuclease P1 enzyme (Yamasa Corp., Chiba, Japan) and alkaline phosphatase (Sigma-Aldrich Chemical Co., St. Louis, MO).…”

Lung as a new target in rats of 2‐amino‐3‐methylimidazo[4,5‐f]quinoline carcinogenesis: Results of a two‐stage model initiated with N‐bis(2‐hydroxypropyl)nitrosamine

“…in a DEN and DMHinitiated two-stage carcinogenesis model. (7) Body weights and food consumption were measured once a week until week 6 and thereafter once every three weeks. All surviving animals were killed under ether anesthesia at the end of week 30.…”

“…(5) Of several carcinogenic HCAs, none have hitherto demonstrated lung carcinogenicity in rats (6) although we recently suggested that IQ might be an exception. (7) Thus, we incidentally found that incidences of alveolar hyperplasias, adenomas and adenocarcinomas in the lung were significantly increased in a group given 300 p.p.m. IQ for 27 weeks after initiation with diethylnitrosamine (DEN) and 1,2-dimethylhydrazine (DMH), as compared with the initiation alone group.…”

“…IQ for 27 weeks after initiation with diethylnitrosamine (DEN) and 1,2-dimethylhydrazine (DMH), as compared with the initiation alone group. (7) DEN is a genotoxic lung carcinogen and it was found to induce lung neoplastic lesions in approximately 50% of rats receiving a single dose (200 mg/kg body weight) in a long-term (103 week) experiment. (8) With regard to mechanisms of IQ carcinogenesis, metabolically activated IQ forms DNA adducts (1,9,10) which have been detected in the lungs as well as in its established target organs in F344 rats.…”

“…(15) Recently, we demonstrated that simultaneous treatment with NaNO 2 enhanced the carcinogenic potential of IQ, especially in the colon and Zymbal's glands of rats with oxidative stress suggested to be partly responsible for the observed enhancement of colon carcinogenesis. (7) Likewise, IQ treatment of Nrf2-gene (transcriptional factor for inducible expression of a group of antioxidant enzymes) knockout mice increased liver tumor formation associated with increase in oxidative stress markers as compared with wild mice (Y. Kitamura et al, unpublished data).…”